This invention relates to a process for the preparation of 7-substituted-3-quinolinecarbonitriles and intermediates useful in a process to prepare 7-substituted-3-quinolinecarbonitriles and pharmaceutically acceptable salts thereof.
Protein kinases are enzymes that catalyze the transfer of a phosphate group from ATP to an amino acid residue, such as tyrosine, serine, threonine, or histidine on a protein. Regulation of these protein kinases is essential for the control of a wide variety of cellular events including proliferation and migration. Specific protein kinases have been implicated in diverse conditions including cancer [Traxler, P. M., Exp. Opin. Ther. Patents, 8, 1599 (1998); Bridges, A. J., Emerging Drugs, 3, 279 (1998)], restenosis [Mattsson, E., Trends Cardiovas. Med. 5, 200 (1995); Shaw, Trends Pharmacol. Sci. 16, 401 (1995)], atherosclerosis [Raines, E. W., Bioessays, 18, 271 (1996)], angiogenesis [Shawver, L. K., Drug Discovery Today, 2, 50 (1997); Folkman, J., Nature Medicine, 1, 27 (1995)] and osteoporosis [Boyce, J. Clin. Invest., 90, 1622 (1992)] and stroke (Paul, R. et al, Nature Medicine, 7(2), 222(2001). An effective preparation of compounds which are inhibitors of protein tyrosine kinases and are useful in the treatment of cancer is important.
The compounds disclosed in WO9843960 (U.S. Pat. No. 6,002,008) are 3-quinolinecarbonitrile derivatives which are inhibitors of protein tyrosine kinases and useful in the treatment of cancer. The aforementioned compounds have been prepared by processes which are effective for the initial preparation of targeted compounds. However, a new and effective alternate source of important intermediates useful in the preparation of 3-quinolinecarbontrile derivatives is desired. Additionally desired is an alternate process to prepare 7-substituted-3-quinolinecarbonitriles.
A further series of new 3-quinolinecarbonitriles which are also highly effective inhibitors of protein tyrosine kinases and useful in the treatment of cancer are disclosed in published application WO 00/18740. Suitable processes for the preparation of 3-quinolinecarbonitriles are described therein, however, there is still a need in the art for yet more suitable methods for the preparation of important intermediates and final products useful in the preparation of 3-quinolinecarbonitriles useful in the treatment of cancer.
Therefore, methods to prepare 7-substituted-3-quinolinecarbonitriles and intermediates to facilitate their preparation are of great value.
It is an object of this invention to provide an alternate process to prepare 7-substituted-3-quinolinecarbonitriles and intermediates useful in a process to prepare 7-substituted-3-quinolinecarbonitriles which are highly effective as inhibitors of protein kinases useful in the treatment of cancer.
It is an object of this invention to provide a novel process for the preparation of 7-substituted-3-quinolinecarbonitriles by displacement of the 7-fluoro group of 7-fluoro-4-(substituted amino)quinolinecarbonitriles.
It is a further object of this invention to provide a novel process for the preparation of 7-substituted-4-oxo-1,4-dihydro-3-quinolinecarbonitriles by displacement of the 7-fluoro group of 7-fluoro-4-oxo-1,4-dihydro-3-quinolinecarbonitriles.
The present invention provides a process for the preparation of 7-substituted-3-quinolinecarbonitriles of Formula (I) 
wherein:
X is selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94NR2xe2x80x2xe2x80x94;
Wxe2x80x2 is H or xe2x80x94OR3;
q is an integer of 0-5;
m is an integer of 0-2;
n is an integer of 2-5;
R1 is an alkyl group of 1 to 6 carbon atoms, a cycloalkyl group of 3 to 10 carbon atoms, or an aryl of 6 to 12 carbon atoms, or heteroaryl ring, said aryl or heteroaryl ring is optionally fused to an additional aryl or heteroaryl ring, wherein heteroaryl is defined as a 5 or 6 membered aromatic ring moiety containing at least one and up to 4 heteroatoms selected from O, S, and N; said aryl or heteroaryl rings optionally fused may optionally be substituted with 1 to 4 substituents independently selected from the group consisting of xe2x80x94J, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH, xe2x80x94SH, xe2x80x94CN, xe2x80x94N3, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94NHC(O)NH2, xe2x80x94C(O)H, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R4, xe2x80x94OR4, xe2x80x94NHR4, xe2x80x94NR4R4, xe2x80x94S(O)mR4, xe2x80x94NHSO2R4, xe2x80x94R5OH, xe2x80x94R5OR4, xe2x80x94R5NH2, xe2x80x94R5NHR4, xe2x80x94R5NR4R4, xe2x80x94R5SH, xe2x80x94R5S(O)mR4, xe2x80x94NHR6OH, xe2x80x94N(R4)R6OH, xe2x80x94N(R4)R6OR4, xe2x80x94NHR6NH2, xe2x80x94NHR6NHR4, xe2x80x94NHR6NR4R4, xe2x80x94N(R4)R6NH2, xe2x80x94N(R4)R6NHR4, xe2x80x94N(R4)R6NHR4R4,xe2x80x94OR6OH, xe2x80x94OR6OR4, xe2x80x94OR6NH2, xe2x80x94OR6NHR4, xe2x80x94OR6NR4R4, xe2x80x94OC(O)R4, xe2x80x94NHC(O)R4, xe2x80x94NHC(O)NHR4, xe2x80x94OR5C(O)R4, xe2x80x94NHR5C(O)R4, xe2x80x94C(O)R4, xe2x80x94C(O)OR4, xe2x80x94C(O)NHR4, xe2x80x94C(O)NR4R4, xe2x80x94R5C(O)H, xe2x80x94R5C(O)R4, xe2x80x94R5C(O)OH, xe2x80x94R5C(O)OR4, xe2x80x94R5C(O)NH2, xe2x80x94R5C(O)NHR4, xe2x80x94R5C(O)NR4R4, xe2x80x94R5OC(O)R4, xe2x80x94R5OC(O)NH2, xe2x80x94R5OC(O)NHR4 and xe2x80x94R5OC(O)NR4R4, and xe2x80x94YR7 groups wherein Y is independently selected from xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94NHC(O)xe2x80x94, xe2x80x94NHSO2xe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94C(OH)Hxe2x80x94, xe2x80x94Q(C(R8)2)q-, xe2x80x94(C(R8)2)q-, xe2x80x94(C(R8)2)qQxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, cis- and trans xe2x80x94CHxe2x95x90CHxe2x80x94 and cycloalkyl of 3-10 carbon atoms;
Q is xe2x80x94Oxe2x80x94, xe2x80x94S(O)mxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94NR9xe2x80x94;
J is halogen selected from fluoro, chloro, bromo and iodo;
R2, R2xe2x80x2 and R3 are each independently selected from an alkyl group of 1 to 6 carbon atoms, an alkenyl group of 2 to 6 carbon atoms or an alkynyl group of 2 to 6 carbon atoms, wherein each independent alkyl, alkenyl or alkynyl group is optionally substituted with xe2x80x94NO2, cyano, or xe2x80x94QR4, or R2, R2 and R3 are each independently selected from xe2x80x94(C(R8)2)q-aryl, xe2x80x94(C(R8)2)q-heteroaryl, xe2x80x94(C(R8)2)q-heterocyclyl, xe2x80x94(C(R8)2)nxe2x80x94Qxe2x80x94(C(R8)2)q-aryl, xe2x80x94(C(R8)2)nxe2x80x94Qxe2x80x94(C(R8)2)q-heteroaryl, xe2x80x94(C(R8)2)nxe2x80x94Qxe2x80x94(C(R8)2)q-heterocyclyl, xe2x80x94(C(R8)2)nxe2x80x94Qxe2x80x94(C(R8)2)nxe2x80x94Q-aryl, xe2x80x94(C(R8)2)nxe2x80x94Qxe2x80x94(C(R8)2)nxe2x80x94Q-heteroaryl, and xe2x80x94(C(R8)2)nxe2x80x94Qxe2x80x94(C(R8)2)nxe2x80x94Q-heterocyclyl, wherein the heterocyclyl group may optionally be substituted on carbon or nitrogen with a group selected from xe2x80x94R4, xe2x80x94(C(R8)2)q-aryl, xe2x80x94(C(R8)2)q-heteroaryl, xe2x80x94(C(R8)2)q-heterocyclyl, xe2x80x94(C(R8)2)qxe2x80x94SO2R4, or the heterocyclyl group may optionally be substituted on carbon by xe2x80x94(C(R8)2)qxe2x80x94QR4, or the heterocyclyl group may optionally be substituted on nitrogen by xe2x80x94(C(R8)2)nxe2x80x94QR4, and also wherein the aryl or heteroaryl group may optionally be substituted with a group selected from xe2x80x94NO2, cyano, xe2x80x94R4, xe2x80x94(C(R8)2)q-aryl, xe2x80x94(C(R8)2)q-heteroaryl, xe2x80x94(C(R8)2)q-heterocyclyl, xe2x80x94(C(R8)2)qxe2x80x94SO2R4, and xe2x80x94(C(R8)2)qxe2x80x94QR4 and further provided that R2 and R2xe2x80x2 may optionally be taken together with the nitrogen to which they are attached, forming a heterocyclic ring, that optionally contains an additional heteroatom, selected from nitrogen, oxygen and sulfur, wherein said formed heterocyclic ring may optionally be substituted on carbon or nitrogen with a group xe2x80x94R4, or said heterocyclic ring may optionally be substituted on carbon by xe2x80x94(C(R8)2)qxe2x80x94QR4, or said heterocyclic ring may optionally be substituted on nitrogen by xe2x80x94(C(R8)2)nxe2x80x94QR4;
R4 is a monovalent group independently selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms;
R5 is a divalent group independently selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms;
R6 is a divalent alkyl group of 2 to 6 carbon atoms;
R7 is a cycloalkyl ring of 3 to 10 carbon atoms optionally substituted with one or more alkyl groups of 1 to 6 carbon atoms or an aryl or heteroaryl ring, optionally fused to an additional aryl or heteroaryl ring, wherein said aryl or heteroaryl ring optionally fused, may optionally be substituted with 1 to 4 substituents selected from the group consisting of aryl, xe2x80x94CH2-aryl, xe2x80x94NH-aryl, xe2x80x94O-aryl, xe2x80x94S(O)m-aryl, xe2x80x94J, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OH, xe2x80x94SH, xe2x80x94CN, xe2x80x94N3, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94NHC(O)NH2, xe2x80x94C(O)H, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94R4, xe2x80x94OR4, xe2x80x94NHR4, xe2x80x94NR4R4, xe2x80x94S(O)mR4, xe2x80x94NHSO2R4, xe2x80x94R5OH, xe2x80x94R5OR4, xe2x80x94R5NHR2, xe2x80x94R5NHR4, xe2x80x94R5NR4R4, xe2x80x94R5SH, xe2x80x94R5S(O)mR4, xe2x80x94NHR6OH, xe2x80x94NHR6OR4, xe2x80x94N(R4)R6OH, xe2x80x94N(R4)R6OR4, xe2x80x94NHR6NH2, xe2x80x94NHR6NHR4, xe2x80x94NHR6NR4R4, xe2x80x94N(R4)R6NH2, xe2x80x94N(R4)R6NHR4, xe2x80x94N(R4)R6NHR4R4, xe2x80x94OR6OH, xe2x80x94OR6OR4, xe2x80x94OR6NH2, xe2x80x94OR6NHR4, xe2x80x94OR6NR4R4, xe2x80x94OC(O)R4, xe2x80x94NHC(O)R4, xe2x80x94NHC(O)NHR4, xe2x80x94OR5C(O)R4, xe2x80x94NHR5C(O)R4, C(O)R4, xe2x80x94C(O)OR4, xe2x80x94C(O)NHR4, xe2x80x94C(O)NR4R4, xe2x80x94R5C(O)H, xe2x80x94R5C(O)R4, xe2x80x94R5C(O)OH, xe2x80x94R5C(O)OR4, xe2x80x94R5C(O)NH2, xe2x80x94R5C(O)NHR4, xe2x80x94R5C(O)NR4R4, xe2x80x94R5OC(O)R4, xe2x80x94R5OC(O)NH2, xe2x80x94R5OC(O)NHR4 and xe2x80x94R5OC(O)NR4R4;
R8 is independently xe2x80x94H or xe2x80x94R4;
R9 is a monovalent alkyl group of 1 to 6 carbon atoms; and
pharmaceutically acceptable salts thereof;
which comprises the steps of:
a) reacting a 7-fluoro-4-oxo-1,4-dihydro-3-quinolinecarbonitrile of Formula (II) 
xe2x80x83with a halogenating reagent of the formula PO(Z)3 to provide a 7-fluoro-3-quinolinecarbonitrile 1 where Z is Cl or Br 
b) reacting a 7-fluoro-3-quinolinecarbonitrile of formula 1 of step a) with an amine of the formula R1NH2, e.g. in the presence of pyridine hydrochloride, to provide a 7-fluoro-4-(substituted amino)-3-quinolinecarbonitrile of formula 2 
c) reacting a 7-fluoro-4-(substituted amino)-3-quinolinecarbonitrile of formula 2 of step b) with a compound of the formula R2XH, where X is selected from xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94NR2xe2x80x2xe2x80x94 and where R2xe2x80x2 and R2 are as defined above or R2 and R2xe2x80x2 may optionally be taken together with the nitrogen to which each is attached to form a heterocyclic ring, and in the presence of a base, when X is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, to provide a 7-substituted-3-quinolinecarbonitrile of Formula (I) 
xe2x80x83and if so desired converting a compound of Formula (I) to a corresponding pharmaceutically acceptable salt by conventional means, and if so desired, converting the corresponding pharmaceutically acceptable salt to a compound of Formula (I) by conventional means.
This invention also relates to a process for the preparation of 7-substituted-3-quinolinecarbonitriles of Formula (I) 
wherein the variables are as defined above, which comprises the step of: reacting a 7-fluoro-4-(substituted amino)-3-quinolinecarbonitrile of formula 2
with a compound of the formula R2XH, where X is selected from xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94NR2xe2x80x2xe2x80x94 and where R2xe2x80x2 and R2 are as defined above or R2 and R2xe2x80x2 may optionally be taken together with the nitrogen to which each is attached, to form a heterocyclic ring, and in the presence of a base, when X is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, to provide a 7-substituted-3-quinolinecarbonitrile of Formula (I), 
and if so desired converting a compound of Formula (I) to a corresponding pharmaceutically acceptable salt by conventional means, and if so desired, converting the corresponding pharmaceutically acceptable salt to a compound of Formula (I) by conventional means.
This invention further relates to a process for the preparation of 7-substituted-3-quinolinecarbonitriles of Formula (I) 
wherein the variables are as defined above,
which comprises the steps of:
a) reacting a 7-fluoro-4-oxo-1,4-dihydro-3-quinolinecarbonitrile of Formula (II) 
xe2x80x83with a compound of the formula R2XH, where X is selected from xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94NR2xe2x80x2xe2x80x94 and where R2xe2x80x2 and R2 are as defined above or R2 and R2xe2x80x2 may optionally be taken together with the nitrogen to which each is attached to form a heterocyclic ring, and in the presence of a base, when X is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, to provide a 7-substituted-4-oxo-1,4-dihydro-3-quinolinecarbonitrile of Formula 3
b) reacting a 7-substituted-4-oxo-1,4-dihydro-3-quinolinecarbonitrile of step a) with a halogenating reagent, e.g. of the formula PO(Z)3, to provide a 7-substituted-4-halo-3-quinolinecarbonitrile 4 where Z is Cl or Br 
c) reacting a 7-substituted-4-halo-3-quinolinecarbonitrile of step b) with an amine R1NH2, e.g., in the presence of pyridine hydrochloride, to afford a 7-substituted-3-quinolinecarbonitrile of Formula (I) 
xe2x80x83and if so desired converting a compound of Formula (I) to a corresponding pharmaceutically acceptable salt by conventional means, and if so desired, converting the corresponding pharmaceutically acceptable salt to a compound of Formula (I) by conventional means.
The invention further relates to a process for the preparation of 7-substituted-4-oxo-1,4-dihydro-3-quinolinecarbonitrile of Formula 3
wherein the variables are as defined above,:
which comprises the step of:
reacting a 7-fluoro-4-oxo-1,4-dihydro-3-quinolinecarbonitrile of Formula (II) 
with a compound of the formula R2XH, where X is selected from xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94NR2xe2x80x2xe2x80x94 and where R2xe2x80x2 and R2 may optionally be taken together with the nitrogen to which each is attached, to form a heterocyclic ring, and in the presence of a base, when X is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, to provide a 7-substituted-4-oxo-1,4-dihydro-3-quinolinecarbonitrile of Formula 3. 